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Heterotrimeric G-protein Signaling Is Critical to Pathogenic Processes in Entamoeba histolytica
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Heterotrimeric G-protein Signaling Is Critical to Pathogenic Processes in Entamoeba histolytica
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Journal Article
Heterotrimeric G-protein Signaling Is Critical to Pathogenic Processes in Entamoeba histolytica
2012
Overview
Heterotrimeric G-protein signaling pathways are vital components of physiology, and many are amenable to pharmacologic manipulation. Here, we identify functional heterotrimeric G-protein subunits in Entamoeba histolytica, the causative agent of amoebic colitis. The E. histolytica Gα subunit EhGα1 exhibits conventional nucleotide cycling properties and is seen to interact with EhGβγ dimers and a candidate effector, EhRGS-RhoGEF, in typical, nucleotide-state-selective fashions. In contrast, a crystal structure of EhGα1 highlights unique features and classification outside of conventional mammalian Gα subfamilies. E. histolytica trophozoites overexpressing wildtype EhGα1 in an inducible manner exhibit an enhanced ability to kill host cells that may be wholly or partially due to enhanced host cell attachment. EhGα1-overexpressing trophozoites also display enhanced transmigration across a Matrigel barrier, an effect that may result from altered baseline migration. Inducible expression of a dominant negative EhGα1 variant engenders the converse phenotypes. Transcriptomic studies reveal that modulation of pathogenesis-related trophozoite behaviors by perturbed heterotrimeric G-protein expression includes transcriptional regulation of virulence factors and altered trafficking of cysteine proteases. Collectively, our studies suggest that E. histolytica possesses a divergent heterotrimeric G-protein signaling axis that modulates key aspects of cellular processes related to the pathogenesis of this infectious organism.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Biology
/ Entamoeba histolytica - enzymology
/ Entamoeba histolytica - genetics
/ Entamoeba histolytica - immunology
/ Gene Expression Regulation - immunology
/ GTP-Binding Protein alpha Subunits - chemistry
/ GTP-Binding Protein alpha Subunits - genetics
/ GTP-Binding Protein alpha Subunits - immunology
/ Guanine Nucleotide Exchange Factors - chemistry
/ Guanine Nucleotide Exchange Factors - genetics
/ Guanine Nucleotide Exchange Factors - immunology
/ Humans
/ Kinases
/ Proteins
/ Protozoan Proteins - chemistry
/ Protozoan Proteins - genetics
/ Protozoan Proteins - immunology
/ Rho Guanine Nucleotide Exchange Factors
/ Transcription, Genetic - immunology
/ Virulence Factors - biosynthesis
